Protein markers of ovarian cancer and its subtypes: insights from proteome-wide Mendelian randomisation analysis

Abstract

Background: Ovarian cancer (OC) is often diagnosed at an advanced stage when prognosis is poor. We aimed to identify blood plasma proteins predictive of OC risk. Methods: We conducted proteome-wide Mendelian randomisation (MR) analyses using summary-level protein quantitative trait locus data covering 2337 plasma proteins, and genome-wide association data on OC and its subtypes (up to 25,509 cases) from the Ovarian Cancer Association Consortium. Wald ratio or inverse-variance weighted MR analysis was used as the primary method, depending on the number of instruments. We evaluated pleiotropy using MR-Egger intercept test and leave-one-out analysis. Results: From 2337 plasma proteins, 12 were associated (p < 7.4 × 10−5) with OC or its subtypes. Robust evidence linked follitropin subunit beta (FSHB) with endometrioid OC (per SD higher, OR 2.41, 95% CI 1.56, 3.71). Associations for the other 11 proteins could be explained by pleiotropy from ABO or MAPT-AS1 loci. We identified 12 suggestive associations with OC or its subtypes at nominal threshold (p < 0.05), involving 11 plasma proteins, with no evidence of pleiotropy from leave-one-out and MR-Egger intercept tests (Pintercept > 0.17). Potential drug targets were identified for follitropin receptor and eight other proteins. Conclusion: Our study suggests FSHB and 11 additional plasma proteins as of potential interest in OC (or subtypes) prognosis, mostly representing potentially druggable targets. (Figure presented.)